Fatty acid-regulated transcription factors in the liver.

Nutrition Program, School of Biological and Population Health Science, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA. Donald.Jump@oregonstate.edu

Abstract

Fatty acid regulation of hepatic gene transcription was first reported in the early 1990s. Several transcription factors have been identified as targets of fatty acid regulation. This regulation is achieved by direct fatty acid binding to the transcription factor or by indirect mechanisms where fatty acids regulate signaling pathways controlling the expression of transcription factors or the phosphorylation, ubiquitination, or proteolytic cleavage of the transcription factor. Although dietary fatty acids are well-established regulators of hepatic transcription factors, emerging evidence indicates that endogenously generated fatty acids are equally important in controlling transcription factors in the context of glucose and lipid homeostasis. Our first goal in this review is to provide an up-to-date examination of the molecular and metabolic bases of fatty acid regulation of key transcription factors controlling hepatic metabolism. Our second goal is to link these mechanisms to nonalcoholic fatty liver disease (NAFLD), a growing health concern in the obese population.

The role of endogenous fatty acid metabolism in the control of hepatic gene transcription. The generation of fatty acids within hepatic parenchymal cells affects the control of at least three transcription factors, peroxisome proliferator-activated receptor α(PPARα), sterol regulatory element–binding protein 1 (SREBP-1), and forkhead box O1 (FoxO1). The mechanisms include the production of fatty acids by de novo lipogenesis (DNL) and monounsaturated fatty acid (MUFA) (18:1, ω7) and polyunsaturated fatty acid (PUFA) (C20–22 ω3 and ω6 PUFA) synthesis. SREBP-1 nuclear abundance is well suppressed by C20–22 PUFA, and hepatic conversion of essential fatty acids to C20–22 PUFA suppresses SREBP-1 nuclear abundance and DNL. Because this pathway produces both C20 and C22 PUFAs, PPARα signaling can be affected. C20 PUFAs, but not C22 PUFAs, are robust activators of PPARα. FoxO1 activity is not affected by exogenous fatty acids or endogenous production of PUFAs. FoxO1 nuclear abundance, however, is regulated by mechanisms that control hepatic conversion of palmitoleic acid (16:1, ω7) to cis-vaccenic acid (18:1, ω7). Increased hepatic production of 18:1, ω7 induces production of rictor, a component of mTORC2. mTORC2 phosphorylates Akt-S473, and active Akt phosphorylates FoxO1-S256. Phospho-FoxO1 is excluded from nuclei and degraded in the proteasome. The outcome is suppressed expression of genes involved in gluconeogenesis (GNG) and hepatic glucose production (HGP). The up ( green) and down (red ) block arrows represent induction or repression of the pathway or transcription factor. Abbreviations: CTE1, cytosolic thioesterase-1; CYP4A, cytochrome P450-4A; Elovl, fatty acid elongase; G6Pase, glucose-6 phosphatase; mRNA, messenger ribonucleic acid; Pck1, phosphoenolpyruvate carboxykinase.